Antimicrobial resistance stimulates the search for antimicrobial forms that may be less subject to acquired resistance. Here we report a conceptual design of protein pseudocapsids exhibiting a broad spectrum of antimicrobial activities. Unlike conventional antibiotics, these agents are effective against phenotypic bacterial variants, while clearing “superbugs” in vivo without toxicity. The design adopts an icosahedral architecture that is polymorphic in size, but not in shape, and that is available in both l and d epimeric forms. Using a combination of nanoscale and single-cell imaging we demonstrate that such pseudocapsids inflict rapid and irreparable damage to bacterial cells. In phospholipid membranes they rapidly convert into nanopores, which remain confined to the binding positions of individual pseudocapsids. This mechanism ensures precisely delivered influxes of high antimicrobial doses, rendering the design a versatile platform for engineering structurally diverse and functionally persistent antimicrobial agents.

Graphical Abstract Highlights d An automated spike sorting method for dense, large-scale recordings is presented d Efficient data representation enables sorting of thousands of channels d Automated unit selection through model-based quality control d Conventional spike sorting frequently fails under non-optimal signal conditions Correspondence m.hennig@ed.ac.uk In Brief Data volume and complexity make spike sorting for large-scale extracellular recordings computationally extremely challenging. Hilgen et al. introduce a method enabling analysis of recordings with thousands of channels and provide tools for automated quality control and unit selection. SUMMARY We present a method for automated spike sorting for recordings with high-density, large-scale multielec-trode arrays. Exploiting the dense sampling of single neurons by multiple electrodes, an efficient, low-dimensional representation of detected spikes consisting of estimated spatial spike locations and dominant spike shape features is exploited for fast and reliable clustering into single units. Millions of events can be sorted in minutes, and the method is parallel-ized and scales better than quadratically with the number of detected spikes. Performance is demonstrated using recordings with a 4,096-channel array and validated using anatomical imaging, optoge-netic stimulation, and model-based quality control. A comparison with semi-automated, shape-based spike sorting exposes significant limitations of conventional methods. Our approach demonstrates that it is feasible to reliably isolate the activity of up to thousands of neurons and that dense, multi-channel probes substantially aid reliable spike sorting.

SUMMARYWe present a method for automated spike sorting for recordings with high-density, large-scale multielectrode arrays. Exploiting the dense sampling of single neurons by multiple electrodes, an efficient, lowdimensional representation of detected spikes consisting of estimated spatial spike locations and dominant spike shape features is exploited for fast and reliable clustering into single units. Millions of events can be sorted in minutes, and the method is parallelized and scales better than quadratically with the number of detected spikes. Performance is demonstrated using recordings with a 4,096-channel array and validated using anatomical imaging, optogenetic stimulation, and model-based quality control. A comparison with semi-automated, shape-based spike sorting exposes significant limitations of conventional methods. Our approach demonstrates that it is feasible to reliably isolate the activity of up to thousands of neurons and that dense, multi-channel probes substantially aid reliable spike sorting.

This paper presents the concept of a technology for the automation of laser incisions on soft tissue, especially for application in Transoral Laser Microsurgery (TLM) interventions. The technology aims at automatically controlling laser incisions based on high-level commands from the surgeon, i.e. desired incision shape, length and depth. It is based on a recently developed robotic laser microsurgery platform, which offers the controlled motion of the laser beam on the surgical site. A feed-forward controller provides (i) commands to the robotic laser aiming system and (ii) regulates the parameters of the laser source to achieve the desired results. The controller for the incision depth is extracted from experimental data. The required energy density and the number of passes are calculated to reach the targeted depth. Experimental results demonstrate that targeted depths can be achieved with [Formula: see text]m accuracy, which proves the feasibility of this approach. The proposed technology has the potential to facilitate the surgeon’s control over laser incisions.

We study a brane-world cosmological scenario with local inhomogeneities represented by black holes. The brane is asymmetrically embedded into the bulk. The black strings/cigars penetrating the Friedmann brane generate a Swiss-cheese type structure. This universe forever expands and decelerates, as its general relativistic analogue. The evolution of the cosmological fluid however can proceed along four branches, two allowed to have positive energy density, one of them having the symmetric embedding limit. On this branch a future pressure singularity can arise for either (a) a difference in the cosmological constants of the cosmological and black hole brane regions (b) a difference in the left and right bulk cosmological constants. While the behaviour (a) can be avoided by a redefinition of the fluid variables, (b) establishes a critical value of the asymmetry over which the pressure singularity occurs. We introduce the pressure singularity censorship which bounds the degree of asymmetry in the bulk cosmological constant. We also show as a model independent generic feature that the asymmetry source term due to the bulk cosmological constant increases in the early universe. In order to obey the nucleosynthesis constraints, the brane tension should be constrained therefore both from below and from above. With the maximal degree of asymmetry obeying the pressure singularity censorship, the higher limit is 10 times the lower limit. The degree of asymmetry allowed by present cosmological observations is however much less, pushing the upper limit to infinity.

Antibiotics act against bacterial pathogens by inhibiting their growth or killing them directly. Different modes of action determine different antibacterial responses, whereas phenotypic differences in bacteria can challenge the efficacy of antibiotics.

We study the evolution of a closed Friedmann brane perturbed by the Hawking radiation escaping a bulk black hole. The semi-transparent brane absorbs some of the infalling radiation, the rest being transmitted across the brane to the other bulk region. We characterize the cosmological evolution in terms of the transmission rate ε. For small values of ε a critical-like behaviour could be observed, when the acceleration due to radiation pressure and the deceleration induced by the increasing self-gravity of the brane roughly compensate each other, and cosmological evolution is approximately the same as without radiation. Lighter (heavier) branes than those with the critical energy density will recollapse slower (faster). This feature is obstructed at high values of ε, where the overall effect of the radiation is to speed up the recollapse. We determine the maximal value of the transmission rate for which the critical-like behaviour is observed. We also study the effect of transmission on the evolution of different source terms of the Friedmann equation. We conclude that among all semi-transparent branes the slowest recollapse occurs for light branes with total absorption.

Electron microscopy plays an important role in the analysis of functional nano-to-microstructures. Substrates and staining procedures present common sources of variation for the analysis. However, systematic investigations on the impact of these sources on data interpretation are lacking. Here we pinpoint key determinants associated with reproducibility issues in the imaging of archetypal protein assemblies, protein shells, and filaments. The effect of staining on the morphological characteristics of the assemblies was assessed to reveal differential features for anisotropic (filaments) and isotropic (shells) forms. Commercial substrates and coatings under the same staining conditions gave comparable results for the same model assembly, while highlighting intrinsic sample variations including the density and heterogenous distribution of assemblies on the substrate surface. With no aberrant or disrupted structures observed, and putative artefacts limited to substrate-associated markings, the study emphasizes that reproducible imaging must correlate with an optimal combination of substrate stability, stain homogeneity, accelerating voltage, and magnification.